Human respiratory syncytial virus (HRSV) is a negative-sense, single stranded, RNA paramyxovirus (K M. Empey, et al., Rev. Anti-Infective Agents, 2010, 50(1 May), 1258-1267). RSV is a major cause of respiratory illness in patients of all ages. In adults, it tends to cause mild cold symptoms. In school-aged children, it can cause a cold and bronchial cough. However, in infants and toddlers the virus can cause lower respiratory tract infections including bronchiolitis (inflammation of the smaller airways of the lungs) or pneumonia with many of them requiring hospitalization. It has also been found to be a frequent cause of middle ear infections (otitis media) in pre-school children. RSV infection in the first year of life has been implicated in the development of asthma during childhood.
There are known high-risk groups that infection with RSV is more likely to progress into the acute lower respiratory tract infections (ALRI). Premature infants and/or infants suffering from lung or cardiac disease are at the highest risk to develop ALRI. Additional high-risk groups include the elderly, adults with chronic heart and/or lung disease, stem cell transplant patients and the immunosuppressed.
Currently, there is no vaccine available to prevent HRSV infection. Palivizumab is a monoclonal antibody that is used prophylactically to prevent HRSV infection in high risk infants, e.g. premature infants, and infants with cardiac and/or lung disease. The high cost of Palivizumab treatment limits its use for general purposes. Ribavirin has also been used to treat HRSV infections, but its effectiveness is limited. There is a major medical need for new and effective HRSV treatments that can be used generally by all population types and ages.
There have been several RSV fusion inhibitors that have been disclosed in the following publications: WO2010/103306, WO2012/068622, WO2013/096681, WO2014/060411, WO2013/186995, WO2013/186334, WO 2013/186332, WO 2012 080451, WO 2012/080450, WO2012/080449, WO 2012/080447, WO 2012/080446, and J. Med. Chem. 2015, 58, 1630-1643. Examples of other N-protein inhibitors for treatment of HRSV have been disclosed in the following publications: WO 2004/026843, WO2017/015449, J. Med. Chem. 2006, 49, 2311-2319, and J. Med. Chem. 2007, 50, 1685-1692. Examples of L-protein inhibitors for HRSV have been disclosed in the following publications: WO2017/123884, WO 2011/005842, WO 2005/042530, Antiviral Res. 2005, 65, 125-131, and Bioorg. Med. Chem. Lett. 2013, 23, 6789-6793. Examples of nucleosides/polymerase inhibitors have been disclosed in the following publications: WO 2013/242525 and J. Med. Chem. 2015, 58, 1862-1878.
There is a need for the development of effective treatments for HRSV. Particular, benzodiazepine derivatives are known to be active against RSV. Research has shown that activity resides in one enantiomer of a racemic mixture. Most previously known synthetic routes to the active isomer employ conventional resolution techniques, i.e. treatment with a chiral acid and separation of the diastereoisomeric salt by crystallization or chromatography, but this is impractical on an industrial scale because typically 50% of the undesired enantiomer is discarded unless there is a method to recycle it. In recent years several groups have utilized the approach first published in 1987 by Merck that demonstrated that the mixture of diastereoiosomeric salts could undergo spontaneous racemization in-situ by treating with a catalytic amount of an aromatic aldehyde such as 3,5-dichlorosalicylaldehyde, resulting in a crystallization induced dynamic resolution of the racemate to afford a single enantiomer, Reider, P. J.; Davis, P.; Hughes, D. L.; Grabowski, E. J. J. J. Org. Chem. 1987, 52, 955. A significant proportion of the examples reported in the literature employing either approach (described above) rely on the amide nitrogen being protected prior to the resolution and subsequently de-protected later in the synthesis thereby decreasing the efficiency of the overall process. (WO 2005/090319 A1).
Examples where the resolution is conducted on derivatives with an unprotected amide are limited and require conducting the resolution at elevated temperature. BMS reported in 2016 (OPRD) such an example, resolution of a benzoazepin-6-one conducted in aq. toluene at 100° C. for 12 hours in the presence of catalytic 3,5-dichlorosalicylaldehyde. Merck reported in 1994 (Armstrong, III, J. D.; Eng, K. K.; Keller, J. L.; Purick, R. M.; Hartner, Jr., F. W.; Choi, W-B.; Askin, D.; Volante, R. P., Tetrahedron Letters, 1994, 35, 3239-3242) the resolution of a benzoazepin-2-one in aq. isopropanol at 70° C. for 120 hours with catalytic 5-nitrosalicylaldehyde. There is a need for more efficient and milder ways to resolve the active benzodiazepine from its racemate.